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EP4302755B1 - Formulation de palbociclib contenant un acide aminé - Google Patents

Formulation de palbociclib contenant un acide aminé

Info

Publication number
EP4302755B1
EP4302755B1 EP22183702.4A EP22183702A EP4302755B1 EP 4302755 B1 EP4302755 B1 EP 4302755B1 EP 22183702 A EP22183702 A EP 22183702A EP 4302755 B1 EP4302755 B1 EP 4302755B1
Authority
EP
European Patent Office
Prior art keywords
palbociclib
pharmaceutically acceptable
acceptable salt
glutamic acid
composition according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP22183702.4A
Other languages
German (de)
English (en)
Other versions
EP4302755A1 (fr
Inventor
Gaurav Bhupendrabhai Mehta
Yogesh Sevaramji Gattani
Vijender Gupta
Manish Chawla
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Lotus Pharmaceutical Co Ltd
Original Assignee
Lotus Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lotus Pharmaceutical Co Ltd filed Critical Lotus Pharmaceutical Co Ltd
Priority to EP22183702.4A priority Critical patent/EP4302755B1/fr
Publication of EP4302755A1 publication Critical patent/EP4302755A1/fr
Application granted granted Critical
Publication of EP4302755B1 publication Critical patent/EP4302755B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame

Definitions

  • Palbociclib-free base and pharmaceutically acceptable salts thereof are disclosed in WO2003062236A .
  • Crystalline form of Palbociclib free base having a specific surface area of ⁇ 2 m 2 /g is described in WO2014128588A .
  • Immediate-release capsules containing Palbociclib free base in crystalline anhydrous Form A are authorized under the brand name Ibrance ® (Pfizer) in EU and US.
  • the marketed Palbociclib capsules comprise 75, 100, or 150 mg of Palbociclib in crystalline anhydrous Form A.
  • Palbociclib is approved or was successfully tested for the treatment of ER+ breast cancer and HR+ breast cancer.
  • WO2016193860A discloses a solid dosage form comprising Palbociclib, a water-soluble acid selected from the group consisting of succinic acid, malic acid and tartaric acid, and a pharmaceutically acceptable carrier.
  • the described solid dosage forms demonstrate excellent storage stability and provide substantially pH-independent delivery of Palbociclib with no significant food effects or adverse interactions with PPIs.
  • WO2022029799A discloses a solid oral dosage form comprising palbociclib and at least one compound selected from the group consisting of sulphur-containing amino acid or peptide.
  • compositions according to the present invention containing Palbociclib (free base and/or pharmaceutically acceptable salt) and glutamic acid or a pharmaceutically acceptable salt thereof, in combination with glucono-delta lactone, demonstrate excellent storage stability, improved dissolution profile and provide substantially pH-independent delivery of Palbociclib with no significant food effect.
  • the pH of the GI tract may vary based on whether a patient or subject is in a fed or fasted state. In general, the gastric residence time of a drug is longer in the presence of food than in the fasted state. If the bioavailability of a drug is significantly affected by the presence or absence of food in the GI tract, the drug is said to exhibit a "food effect". The rate of gastric emptying may also influence the concentration of drugs in solution available for absorption at different sites along the GI tract.
  • the present invention thus provides a pharmaceutical solid composition containing
  • Palbociclib may include e. g. palbociclib isethionate salt.
  • Amino acids include leucine, glycine, alanine, valine, isoleucine, proline, methionine, cysteine, histidine, arginine, lysine, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, and pharmaceutically acceptable salts thereof.
  • the amino acid is selected from the group consisting of cysteine, glycine, proline, aspartic acid, glutamic acid, and pharmaceutically acceptable salts thereof.
  • Glutamic acid and salts thereof are suitable for maintaining acidic pH of the pharmaceutical composition.
  • CAS Number: 90-80-2 IUPAC Name: Glucono-delta-lactone Molecular Formula: Structural Formula: Molecular Weight: 178.14 Synonyms: EINECS Number 202-016-5
  • Glucono-delta-lactone the inner ester of gluconic acid, is formed by the removal of water. Commercially it is produced by an anaerobic fermentation process converting a carbohydrate source into gluconic acid and glucono-delta-lactone. After fermentation, the gluconic acid is separated from GDL by crystallization.
  • Glucono-delta-lactone (GDL) is a convenient substitute for the free acid, especially where, due to the reversibility between the acid and its lactone form, a gradual change in the pH is preferred.
  • the solid composition contains an intragranular phase containing palbociclib or a pharmaceutically acceptable salt thereof, and an extragranular phase containing glutamic acid or pharmaceutically acceptable salt(s) thereof, and glucono-delta lactone.
  • the amount of palbociclib or a pharmaceutically acceptable salt thereof in the solid composition is within the range of 10 to 50 wt. %, preferably 17 to 23 wt. %.
  • the amount of glucono-delta lactone in the solid composition is within the range of 4 to 15 wt. %,-preferably 5 to 7 wt. %.
  • the amount of Palbociclib or a pharmaceutically acceptable salt thereof in the solid composition is within the range of 10 to 50 wt. % and the amount of glutamic acid or pharmaceutically acceptable salt thereof is within the range of 3 to 25 wt. %.
  • the amount of Palbociclib or a pharmaceutically acceptable salt thereof in the solid composition is within the range of 10 to 50 wt. %, the amount of glutamic acid or pharmaceutically acceptable salt thereof is within the range of 3 to 25 wt. % and the amount of glucono-delta lactone is within the range of 4 to 15 wt. %.
  • the solid composition of the invention further contains at least one pharmaceutically acceptable excipient, preferably selected from disintegrants, binders, diluents, lubricants, and glidants.
  • Disintegrants may be added to the pharmaceutical granulate composition to promote the breakup of the tablet or capsule into smaller fragments in an aqueous environment, thereby increasing the available surface area and promoting a more rapid release of the active pharmaceutical ingredient.
  • Suitable examples of disintegrants to be used according to the present invention include crospovidone, sodium starch glycolate, croscarmellose sodium, and mixtures of any of the foregoing.
  • Preferred disintegrant is sodium starch glycolate or crospovidone.
  • Disintegrants can be added as intragranular or extragranular excipients. Disintegration occurs by the rapid uptake of water followed by rapid and enormous swelling.
  • the disintegrant When added as an intragranular excipient it helps to break the granules whereas when added as an extragranular excipient it helps the tablet or capsule to disintegrate.
  • the disintegrant is added extra granularly and intragranularly.
  • Diluents are fillers that are used to increase the bulk volume of the pharmaceutical granulate composition. Generally, by combining a diluent with the active pharmaceutical ingredient, the final product is given adequate weight and size to assist in production and handling. Suitable examples of diluents to be used according to the present invention include starch, pregelatinized starch, microcrystalline cellulose, calcium phosphate, lactose, sorbitol, mannitol, and sucrose. According to the preferred embodiment of the invention microcrystalline cellulose and/or lactose are used as diluents.
  • the pharmaceutical composition according to the invention is prepared by using different granulation methods, preferably selected from dry or wet granulation.
  • Dry granulation includes dry mixing, slug-de-slug, and roller compaction processes.
  • Wet granulation includes aqueous granulation and non-aqueous granulation.
  • Other wet granulation technologies like Extrusion - Spherization, Spray drying, Supercritical fluid, Fluid Bed Granulation, Hotmelt Granulation, freeze granulation, Foam Granulation etc. are also suitable.
  • dry granulation or direct compression is used, or granulation followed by filling of capsules.
  • composition form of the invention is preferably formulated as a tablet, a coated tablet or a capsule.
  • the coated tablet may be a film-coated tablet.
  • the tablet may be a bi-layer or a multi-layer tablet.
  • the solid composition of the invention is suitable for use in the treatment of cancer, more specifically in the treatment of ER+ or HR+ breast cancer.
  • Solid compositions comprising Palbociclib, one or more amino acids or salts thereof and optionally a water-soluble acid Glucono-delta-lactone (GDL) are prepared by dry granulation process.
  • GDL water-soluble acid Glucono-delta-lactone
  • the solid composition contains Palbociclib (Free base, preferably with Specific surface area NLT 2.3 m 2 /g specified by BET method), Microcrystalline cellulose (trade name: MCC, FMC), Glucono-delta-lactone (GDL) (trade name: GDL, Roquette), Glutamic acid (Merck), Glutamic acid hydrochloride (Spectrum Chemicals), L-Cysteine Hydrochloride monohydrate (Spectrum), L-Cysteine Hydrochloride Anhydrous (Merck), crospovidone (trade name: VIVAPHARM ® PVPP, JRS pharma), colloidal silicon dioxide (trade name: Aerosil 200 Pharma, Evonik), Magnesium stearate (From Peter Greven) according to the formulation proportions in Table 1.
  • Palbociclib Free base, preferably with Specific surface area NLT 2.3 m 2 /g specified by BET method
  • Microcrystalline cellulose trade name: MCC, FMC
  • GDL Glucono-delta-lactone
  • the intragranular part 1-4 of the composition according to Table 1 was thoroughly mixed using a diffusion mixer, granulated by roller compaction, followed by milling through co-mill 1.2 mm and the final granules were further lubricated.
  • the granules were mixed with the extra granular excipients according to Table 1 and compressed into tablet.
  • the tablet was further coated using Opadry purple.
  • the drug content is about 19 % w/w of the total weight of the coated tablet.
  • Table 1 Strength 125 mg
  • Example 1 Sr No.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (12)

  1. Composition pharmaceutique solide contenant
    - du palbociclib ou un sel pharmaceutiquement acceptable de celui-ci,
    - de l'acide glutamique ou un sel pharmaceutiquement acceptable de celui-ci ; et
    - de la glucono-delta-lactone.
  2. Composition selon la revendication 1, où le palbociclib est présent sous forme de base libre.
  3. Composition selon la revendication 1, où le palbociclib est présent sous forme de base libre sous forme cristalline ayant une surface spécifique (mesurée en BET) d'au moins 2,3 m2/g.
  4. Composition selon la revendication 1, où le sel d'acide glutamique est le chlorhydrate d'acide glutamique.
  5. Composition selon l'une quelconque des revendications précédentes, où la quantité de palbociclib ou d'un sel pharmaceutiquement acceptable de celui-ci dans la composition solide est de 10 à 50 % en poids, de préférence de 17 à 23 % en poids,
    et/ou
    la quantité d'acide glutamique ou d'un sel pharmaceutiquement acceptable de celui-ci dans la composition solide est de 3 à 25 % en poids, de préférence de 6 à 18 % en poids,
    et/ou
    la quantité de glucono-delta-lactone dans la composition solide est de 4 à 15 % en poids, de préférence de 5 à 7 % en poids.
  6. Composition selon l'une quelconque des revendications précédentes, où la quantité de palbociclib ou d'un sel pharmaceutiquement acceptable de celui-ci dans la composition solide est de 17 à 23 % en poids et la quantité d'acide glutamique ou d'un sel pharmaceutiquement acceptable de celui-ci est de 6 à 18 % en poids.
  7. Composition selon l'une quelconque des revendications précédentes, contenant en outre au moins un excipient pharmaceutiquement acceptable, choisi parmi les agents désintégrants, les liants, les diluants, les lubrifiants et les agents glissants.
  8. Composition selon la revendication 7, contenant au moins un désintégrant choisi parmi le glycolate d'amidon sodique et la crospovidone.
  9. Composition solide selon l'une quelconque des revendications 1 à 8, contenant une phase intragranulaire contenant du palbociclib ou un sel pharmaceutiquement acceptable de celui-ci, et une phase extragranulaire contenant de l'acide glutamique ou un sel pharmaceutiquement acceptable de celui-ci, et de la glucono-delta-lactone.
  10. Composition solide selon l'une quelconque des revendications 1 à 8, contenant au moins deux couches: une couche contenant du palbociclib ou un sel pharmaceutiquement acceptable de celui-ci, et une autre couche contenant de l'acide glutamique ou un sel pharmaceutiquement acceptable de celui-ci, et de la glucono-delta-lactone.
  11. Composition solide selon la revendication 9 ou 10, choisie parmi un comprimé, un comprimé enrobé et une capsule, de préférence choisie parmi un comprimé pelliculé, un comprimé bicouche et un comprimé multicouche.
  12. Composition solide selon l'une quelconque des revendications 1 à 11 pour utilisation dans le traitement du cancer, de préférence dans le traitement du cancer du sein ER+ ou HR+.
EP22183702.4A 2022-07-07 2022-07-07 Formulation de palbociclib contenant un acide aminé Active EP4302755B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP22183702.4A EP4302755B1 (fr) 2022-07-07 2022-07-07 Formulation de palbociclib contenant un acide aminé

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
EP22183702.4A EP4302755B1 (fr) 2022-07-07 2022-07-07 Formulation de palbociclib contenant un acide aminé

Publications (2)

Publication Number Publication Date
EP4302755A1 EP4302755A1 (fr) 2024-01-10
EP4302755B1 true EP4302755B1 (fr) 2025-08-20

Family

ID=82403811

Family Applications (1)

Application Number Title Priority Date Filing Date
EP22183702.4A Active EP4302755B1 (fr) 2022-07-07 2022-07-07 Formulation de palbociclib contenant un acide aminé

Country Status (1)

Country Link
EP (1) EP4302755B1 (fr)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR122016021801B8 (pt) 2002-01-22 2021-05-25 Warner Lambert Co compostos 2-(piridin-2-ilamino)-pirido[2,3-d]pirimidin-7-onas
DK1648889T3 (da) 2003-07-11 2009-01-05 Warner Lambert Co Isethionatsalt af en selektiv CDK4-inhibitor
SI3431475T1 (sl) 2013-02-21 2021-08-31 Pfizer Inc. Trdne oblike selektivnega zaviralca CDK4/6
WO2016156070A1 (fr) * 2015-04-02 2016-10-06 Sandoz Ag Particules modifiées de palbociclib
PE20180395A1 (es) 2015-06-04 2018-02-28 Pfizer Formas de dosificacion solidas de palbociclib
WO2021220295A1 (fr) * 2020-04-29 2021-11-04 Natco Pharma Limited Compositions pharmaceutiques à libération immédiate comprenant du palbociclib
BR112023002161A2 (pt) * 2020-08-05 2023-04-04 Aizant Drug Res Solutions Private Limited Formas sólidas de dosagem de palbociclibe

Also Published As

Publication number Publication date
EP4302755A1 (fr) 2024-01-10

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